Fibrin sealant is a biological adhesive composed of fibrinogen and thrombin which is used extensively to assist wound healing and to provide sutureless closure of surgical wounds. Fibrinogen is the main structural protein in blood, responsible for forming clots.
For clot formation to occur, fibrinogen must be proteolytically cleaved and converted into fibrin monomer by thrombin, a serine protease that is converted to its active form by Factor Xa. Fibrin monomers assemble into fibrils and eventually form fibres in a three-dimensional network. The formation of a clot also requires the activity of Factor XIII. Factor XIII is a serine protease which is converted to its active form by thrombin in the presence of calcium. Activated Factor XIII (FXIIIa) then converts the non-covalent bonds between the assembled fibrin monomers into covalent bonds by transamination. This renders the fibrin gel less susceptible to proteolytic digestion by plasmin and also increases the overall strength and stiffness of the gel. Fibrin gel is readily resorbed by enzymatic and phagocytic pathways.
To reproduce this coagulation process in the form of a biological adhesive, the fibrinogen component of fibrin sealant usually contains Factor XIII, and the thrombin component is prepared in calcium chloride solution. The two components are applied either sequentially or simultaneously to the repair site, typically by syringe or by spraying. Fibrin sealant readily adheres to wet surfaces and, once polymerised, becomes a semi-rigid, haemostatic, fluid-tight adhesive capable of holding tissues or materials in the desired configuration.
Currently, fibrin sealant products are applied to the wound site as solutions, e.g. using a dual syringe device, which mixes the fibrinogen and thrombin as they exit. The main drawback of such delivery systems is clot formation within the device, resulting in needle and tube blockages. The dual syringe systems are also awkward to fill and manipulate. Further, if there is inadequate mixing of the fibrinogen and thrombin solutions, only weak clots may form.
Many wound sites ooze, and this can result in significant accumulation of fluid at the site. When solutions of the components of fibrin sealant are applied to such sites, they are often flushed away.
U.S. Pat. No. 4,427,651 discloses a sprayable preparation for accelerated haemostasis and optimised biochemical control of wound closure, containing a powdery mixture of 15-60% by weight of thrombin, 5-80% by weight of a desiccating and stabilising agent (albumin, globulin and/or fibrinogen), and 1-10% by weight of fibrinolysis inhibitor. The powdery mixture is suspended in a low-boiling, anhydrous solvent which is used as a propellant.
WO-A-9213495 discloses a lyophilised fibrinogen powder prepared by precipitation, without control of particle size. The powder is usually hydrated prior to use, with the disadvantages described above. It is also proposed that the powder can be used directly when the vessel or wound to be closed is small, and the blood loss is not rapid. In this case, the reaction is dependent on the presence of endogenous thrombin. In larger wounds, the heavier blood flow will wash away the endogenous material, and clotting will not take place.